The proposal describes a five-year training program for development of a research career in cardiovascular disease, particular in the field of vascular biology and inflammation. The candidate, Dr. Yogendra Kanthi, is a physician-scientist with focused interest in venous disease. The primary mentor (D. Pinsky, vascular biology) and an advisory committee of highly successful, translational scientists with complementary expertise in platelets/thrombosis (M. Holinstat), cardiovascular fluids/biomechanics (D. Michele and S. Takayama) have been assembled to provide the candidate with guidance in career development and investigation. The research environment provides extensive resources, core facilities, and content expertise in a collaborative setting. The career development plan includes didactic courses and seminars. There is an immersive research program designed for the candidate to develop both preliminary data and the requisite skillset in experimental study design, grant writing, and knowledge to transition to independent investigator status, with his own laboratory and R01 funding. In patients who fail medical management of atherosclerotic vascular disease, revascularization by surgical bypass grafts initially restores tissue blood flow. However, the most commonly used autologous human vein bypass grafts carry a disproportionately higher rate of failure than arterial bypass grafts (10-30% per year), characterized by adverse remodeling and stenosis. Vein grafts transplanted into an arterial tree are exposed to arterial patterns of pulsatile distention uncharacteristic of typical venous mechanical stresses which alter vein graft phenotype. The overriding hypothesis of this proposal is that cyclic stretching of vein grafts by pulsatile distension from arterialization promotes venous endothelial inflammation leading to excessive vascular remodeling and obstructive lesions, unless curbed by endogenous mechanisms that suppress vascular inflammation. One potential such mechanism is through endothelial CD39, an enzyme that dissipates extracellular nucleotide danger signals (purines) which are potent activators of inflammation and thrombosis. We recently discovered that CD39 expression is induced by laminar fluid shear stresses and is a potent suppressor of atherogenesis. However, whether CD39 expression responds to another significant biomechanical stimulus- cyclic stretching of the endothelium as seen in vein grafts- is not yet defined. My preliminary data supports the overriding hypothesis that CD39 expression is induced by cyclic stretch as seen in vein graft arterialization. The Specific Aims of the proposal are to: 1) Define the response of arterial and venous endothelial CD39 to varying degrees of cyclic stretch simulating arterialization of vein grafts; 2) Elucidate the molecular mechanisms by which CD39 expression is induced by cyclic stretch with a focus on molecular mechanotransducers interacting with the CD39 promoter; and 3) Define the impact of vascular CD39 in mitigating stretch-induced endothelial dysfunction and accelerated intimal hyperplasia in a murine arterialized vein graft model. The goal of this proposal is to define the role of CD39 in suppressing cyclic stretch-induced venous endothelial stress to enhance our understanding of purinergic signaling in vein graft distention and remodeling. The potential impact of this proposal will be to advance our approaches to improve vein graft patency by leveraging endogenous protective mechanisms and to enhance the career development of a dedication physician-scientist.